Mononuclear phagocytes play a central role in regulating hematopoiesis and phagocyte function. First, they produce hematopoietic growth factors and, secondly, they express interleukin-1 and tumor necrosis factor-alpha gene products which function to induce other cells in the hematopoietic microenvironment to produce multilineage hematopoietic growth factors. Virtually all of the induced hematopoietic growth factors are known to have stimulatory effects not only on the proliferative activity of hematopoietic progenitor cells but on the functional activity of terminally differentiated phagocytes. A convincing body of evidence demonstrates that mononuclear phagocytes are important target of HIV-1 infection, and that proviral integration can alter the regulated production of IL-1. Because regulated expression of CSF an interleukin genes is essential for normal hematopoietic and phagocytic function, and because patients with HIV infection commonly exhibit disorders of both processes, we hypothesize that hematopoietic and phagocyte dysfunction in such patients are the direct result of infection of mononuclear phagocytes by HIV. We will test this hypothesis in the first aim of our studies. Specifically, we will determine the effects of latent HIV infection on both hematopoietic and phagocytic function of mononuclear phagocytes and will determine the molecular mechanisms by which these effects occur. Certain physiologic signals, including GM-CSF, can induce the expression of HIV in latently infected cells. We hypothesize that multiple hematopoietic growth factors and interleukins induce the expression of provirus in latently infected mononuclear phagocytes and that this effect is mediated, at least in part, by the induction of specific viral regulatory proteins or cellular transcription factors known to affect HIV expression. We will test these hypotheses in the second aim of this proposal. Specifically, we will determine the effects of recombinant human hematopoietic growth factors and interleukins on proviral expression by HIV infected mononuclear phagocytes and analyze the molecular mechanisms by which either stimulatory or inhibitory effects occur. The results of our studies should provide a strong rationale for the development of therapeutic strategies which might circumvent progressive hematopoietic dysfunction (Aim 1) without the risk of accelerating HIV infection(AIM 2).